Recently, a new technique for drug administration has recently been studied for the purpose of effectively-delivering a drug to a target portion thereby reducing possible side-effects, i.e., the drug delivery system (DDS). In particular, application of polymers which undergo changes in chemical structure, phase transition, and changes in shape and physical properties responsive to changes in surrounding conditions caused by, for example, a chemical substance, pH, temperature, electric or magnetic field, to a timing control of drug release is actively studied. By using a pharmaceutical preparation comprising such stimulus-responsive high molecular weight compounds, a drug delivery system having various functions can be obtained. For example, the pharmaceutical preparation per se notices a signal generated from physiological changes in the living body, determines an amount of the drug to be released depending upon the degree of physiological changes, and releases the drug or stops the drug release (on-off controlling function).
In particular, a temperature-sensitive drug releasing system using a polymeric material responsive to changes in temperature is capable of releasing the drug when required, for example, by releasing an antipyretic agent only when a patient has fever or external heat is applied, and is extensively studied as a practical DDS. The polymeric materials which have been proposed thus far and which respond to changes in temperature include a gel comprising poly-N-isopropylacrylamide as described in, for example, Okano et al., Hyomen (Surface Science), Vol. 10, p. 90, 1989, and J. Controlled Release, Vol. 11, p. 255, 1990; a gel comprising a copolymer of N-isopropylacrylamide and an alkyl methacrylate as described in, for example, Yoshida et al., Jinko Zoki (Artificial Organs), Vol. 19, p. 1243, 1990, and Drug Delivery System, Vol. 5, p. 279, 1990; an interpenetrating polymer network (IPN) gel comprising polyacrylic acid and polyacrylamide as described in, for example, Katono et al., J. Controlled Release, Vol. 16, p. 215, 1991; and a film comprising a porous film impregnated with liquid crystal molecules as described in, for example, Nozawa et al., J. Controlled Release, Vol. 15, p. 29, 1991. With these polymeric materials, the on-off control of the drug release responsive to changes in temperature is put into practical use by utilizing shrinking or swelling of gel depending upon changes in temperature, or by utilizing difference in permeability at a temperature just below or above the liquid crystal transition temperature.
However, the conventional polymers which respond to changes in temperature, that is, so-called temperature-responsive polymers, have various disadvantages such that they have poor mechanical strength, the temperature for the on-off control can not be optionally set, the polymers remain unchanged when used in the living body. In the case-of liquid crystal impregnated film, the liquid crystal molecule can not be fixed sufficiently and, therefore, the film is unstable in repeated use. For the reasons described above, the conventional temperature-responsive polymers have not yet been put into practical use. In particular, since the on-off control of the drug release is mostly performed in the living body, it is highly desirable to use a material which can be degraded and absorbed in the living body or under natural environmental conditions. However, it has not been proposed to use the biodegradable polymer as a temperature-responsive polymer.
As a result of extensive studies, the present inventors have found a novel temperature-responsive polymer which is degraded and absorbed in the living body or under natural environmental conditions after use and also which is free from problems associated with the conventional materials such that the materials have poor mechanical strength and are difficult to optionally set the temperature at which the on-off control is performed. The novel polymer can be produced by using a polymer which mainly comprises aliphatic polyesters such as polylactide, polyglycollide, poly-.gamma.-butyrolactone, poly-.epsilon.-caprolactone, poly-.beta.-hydroxybutyric acid and poly-.beta.-hydroxyvaleric acid which are known as biodegradable polymers as described in Kobunshi Shin-sozai Binran (Bulletin of Polymeric New Materials), edited by the Society of Polymer Science, Japan, 1989, pp. 322-347, and completed the present invention.